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Myelodysplastic syndrome

Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome

Leukemia volume 31, pages 861–871 (2017)Cite this article

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Abstract

Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2KD/KDEzh2Δ/Δ). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2. Hyper-differentially methylated regions (hyper-DMRs) in Tet2KD/KDEzh2Δ/Δ MDS hematopoietic stem/progenitor cells were largely distinct from those in each single mutant and correlated with transcriptional repression. Although Tet2 hypomorph was responsible for enhancer hypermethylation, the loss of Ezh2 induced hyper-DMRs that were enriched for CpG islands of polycomb targets. Notably, Ezh2 targets largely lost the H3K27me3 mark while acquiring a significantly higher level of DNA methylation than Ezh1 targets that retained the mark. These findings indicate that Ezh2 targets are the major targets of the epigenetic switch in MDS with Ezh2 insufficiency. Our results provide a detailed trail for the epigenetic drift in a well-defined MDS model and demonstrate that the combined dysfunction of epigenetic regulators cooperatively remodels the epigenome in the pathogenesis of MDS.

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Acknowledgements

We thank Haruhiko Koseki (RIKEN, Japan) for providing us with Ezh2 mutant mice. We thank Sekiya T and Yoshimura T (Keio University, Tokyo) for providing us with the eMIGR1 and eMIGR1-Nr4a vectors. We thank Ola Mohammed Kamel Rizq for the critical review of our manuscript. This work was supported in part by Grants-in-Aid for Scientific Research (#15H02544) and Scientific Research on Innovative Areas ‘Stem Cell Aging and Disease’ (#26115002) from MEXT, Japan, and grants from the Uehara Memorial Foundation, Yasuda Memorial Medical Foundation, and Tokyo Biochemical Research Foundation. The super-computing resource was provided by Human Genome Center, the Institute of Medical Science, the University of Tokyo (http://sc.hgc.jp/shirokane.html).

Author contributions

NH and MO performed the experiments, analyzed results, made the figures and actively wrote the manuscript. GS, HM, SK, MO, AS, CW, TM, KT, AK, CN and KY assisted with the experiments. KS provided mice and AI conceived of and directed the project, secured funding and actively wrote the manuscript.

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  1. N Hasegawa and M Oshima: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan

    N Hasegawa, M Oshima, G Sashida, S Koide, A Saraya, C Wang & A Iwama

  2. Department of Hematology, Chiba University Hospital, Chiba, Japan

    N Hasegawa, T Muto & C Nakaseko

  3. Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan

    N Hasegawa, T Muto, C Nakaseko & K Yokote

  4. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

    G Sashida

  5. Department of Molecular Laboratory Medicine, Kumamoto University, Kumamoto, Japan

    H Matsui

  6. College of Life Sciences, Inner Mongolia University, Hohhot, China

    C Wang

  7. Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

    K Takane & A Kaneda

  8. Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    K Shimoda

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  1. N Hasegawa
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Correspondence to A Iwama.

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Hasegawa, N., Oshima, M., Sashida, G. et al. Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome. Leukemia 31, 861–871 (2017). https://doi.org/10.1038/leu.2016.268

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